Amide bonds are key component in many biological materials and known drugs. For example, Atorvastatin, which blocks the production of cholesterol, and Valsartan, a blockade of angiotensin-II receptors, both contain amide bonds. Mild, efficient and general methods for the construction of amide and peptide linkages are desired for the production of therapeutics and biological tools that are based upon peptide, protein, and glycopeptides motifs.
Amide bonds are typically synthesized from the union of carboxylic acids and amines; however, the reaction between these two functional groups is not spontaneous at ambient temperature, with the elimination of water only taking place at extremely high temperatures (>200° C.), conditions which are typically detrimental to the integrity of the reacting compounds themselves.
Some coupling methods used to generate amide bonds from carboxylic acids and amines utilize special activating protocols or the construction of special functionalities such as azides and ketoacids or hydroxylamines. There are a number of ‘coupling reagents’ which convert the —OH of the carboxylic acid to a good leaving group prior to the treatment with the amine. Classical reagents include carbodiimides, phosphonium salts, uronium salts and reagents generating acid halides.
Generating amine reactive acid halides, using reagents such as thionyl chloride and phosphorus pentachloride, is not compatible with many synthetic strategies, due to the formation of hydrochloric acid. Newer reagents used to generate acid halides such as Deoxo-Fluor and DAST are expensive, hazardous, and require purification by chromatography after the reaction.
Carbodiimides such as dicyclohexylcarbodiimide (DCC) are commonly used as coupling reagents; however, these reagents need to be used in conjunction with additives such as 1-hydroxy-1H-benzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) in order to decrease undesired epimerization that can occur when using chiral amino acids. These additives yield by-products that catalyze the ‘dimerization’ of DCC. In addition to this, safety considerations have to be carefully considered when using benzotriazoles (or variants thereof) because of their explosive properties.
The coupling reagents based on the HOBt/HOAt system, such as uronium/aminium salts like HATU react with the carboxylic acids to form active esters; however, side reactions of the coupling reagents with the amines lead to the formation of guanidinium side products. The phosphonium salts, which are also based on HOBt/HOAt, such as BOP are undesirable due to the carcinogenic and respiratory toxicity associated with HMPA generated in the reaction.
More recent approaches to amide bond formation include Staudinger ligation, a modification of the Staudinger reaction which produces an amide linked product from the reaction of a modified triarylphosphine and azides, as well as the further modified version which involves the reaction of thioacids with azides. Another method is the ‘native chemical ligation’ method which is used for the preparation of proteins. It involves the reaction between a peptide alpha-thioester and a cysteine-peptide, to yield a product with a native amide bond at the ligation site. However, the thioalkyl esters are rather unreactive and despite the use of a catalyst the reaction typically takes 24-28 hours.
Although the above methodologies have been applied to the synthesis of proteins and protein analogues, there is a continued interest in the wider application of the tools of organic chemistry to the study of proteins. Despite the number of coupling reagents that have been reported, most reagents are simply not efficient for a broad range of amide bond forming reactions. Thus, there remains a need for simple, effective reagents with high conversions and low levels of epimerization of chiral compounds that produces limited by-products.
Certain catalytic dehydrative condensation reactions are reported by the reaction of carboxylic acids and phosphoric acids with alcohols and amines to give esters and amides. See Funatomi et al., Green Chem. 2006, 8, 1022; Ishihara, Tetrahedron 2009, 65, 1085; and Sakakura et al., JACS 2007, 129, 14775.